Noncontrast Magnetic Resonance Angiography in the Era of Nephrogenic Systemic Fibrosis and Gadolinium Deposition.

ABSTRACT: Gadolinium-based contrast agents for clinical magnetic resonance imaging are overall safe. However, the discovery of nephrogenic systemic fibrosis in patients with severe renal impairment and gadolinium deposition in patients receiving contrast have generated developments in contrast-free imaging of the vasculature, that is, noncontrast magnetic resonance angiography. This article presents an update on noncontrast magnetic resonance angiography techniques, with comparison to other imaging alternatives. Potential benefits and challenges to implementation, and evidence to date for various clinical applications are discussed.

Erythema nodosum masking nephrogenic systemic fibrosis as initial skin manifestation.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a complication of the gadolinium-based contrast agent used in imaging studies. It is typically characterised by hard, erythematous and indurated skin plaques with surrounding subcutaneous oedema. Distinct papules and subcutaneous nodules can also be seen. Fibrocytes in NSF are immunohistochemically positive for CD34. CASE PRESENTATION: We present a case of NSF occurred after gadolinium exposure in which the initial presentation mimics an erythema nodosum (EN)-like picture. An initial skin biopsy showed EN. Subsequently the patient developed progressive skin and joints contracture. A repeated skin biopsy done three months later confirmed the diagnosis of NSF. As far as we are aware, this is the second reported case of NSF that mimicked the presentation of EN in the early phase of the disease. CONCLUSIONS: The appearance of EN-like disease can be one of the early manifestations of NSF. We hope that early recognition of this unusual presentation can alert the physician or nephrologist to the potential diagnosis of NSF.

Preliminary experience with intravenous gadoxetate disodium as a craniospinal MR contrast agent.

INTRODUCTION: Gadoxetate disodium is a gadolinium-based contrast agent (GBCA) typically used for body imaging, as about 50% of its excretion is via the liver. Its use for craniospinal MRI has not been reported. MATERIALS AND METHODS: Over a 3 years period, 31 adults underwent postcontrast MRI using gadoxetate disodium, each of whom had a relative contraindication to a GBCA, but a GBCA was deemed necessary by the clinical service to direct therapy. Postcontrast T1WI included either gradient-echo (GET1WI, n=12) or spin-echo (SET1WI, n=13) imaging. The contraindication in 29 patients was stage 3-5 chronic kidney disease (CKD) or acute kidney injury (AKI); the other two had normal kidney function, but a history of a reaction to another GBCA (vomiting in one and hypersensitivity in the other). Over a 3 years period, in those patients in whom a GBCA was both deemed necessary and had an estimated GFR (eGFR) of <40 ml/min/1.73 m(2) (i.e., stage 3-5 CKD), both informed consent and nephrology consultation was obtained. A 10 ml dose was given for cranial (n=23), spinal (n=9), and neck/face MRI (n=3), as well as craniocervical MRA (n=6). Three neuroradiologists separately evaluated for normal enhancement in 11 structures. The contrast enhancing percentage (CE%) was measured in 3 structures, and in enhancing lesions, if present. RESULTS: The pre-MRI eGFR was not significantly different from that at 30-90 days (p=0.522) in the 23 patients with an available eGFR at >90 days post-MRI; no patients developed acute kidney injury post-MRI, nor nephrogenic systemic fibrosis. Of the 11 intracranial structures scored, the superior sagittal sinus, pituitary stalk, and atrial choroid plexus enhanced in all 23 patients who underwent brain MRI, with CE%'s of 171.0%, 73.0%, and 69.8%, respectively. The number of patients with enhancing lesions were 3/23 brain MRI's, 8/9 spinal MRI's, 3/3 neck MRI's, and 2/6 craniocervical MRA/MRV's. In 9 spinal MRI's, the basivertebral plexus CE% was 213.7%; in the 7 with spondylodiscitis, the CE% measured 125.8% in enhancing epidural tissue, with a contrast-to-noise ratio (CNR) of 98.0%. CONCLUSION: This preliminary report describes the use of gadoxetate disodium as an alternative GBCA for craniospinal MRI and MRA in the renally impaired, but its efficacy in this regard must be further evaluated prospectively.

Nephrogenic systemic fibrosis risk after liver magnetic resonance imaging with gadoxetate disodium in patients with moderate to severe renal impairment: results of a prospective, open-label, multicenter study.

OBJECTIVE: The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment. MATERIALS AND METHODS: We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. RESULTS: A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up. CONCLUSIONS: Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed.

Superior vena cava obstruction associated with nephrogenic systemic fibrosis.

A 56-year-old woman with hypertension-induced end stage renal disease presented with skin thickening and mottled discoloration. Cutaneous biopsy showed increased dermal fibroblasts embedded in fibromyxoid stroma with scattered perivascular and interstitial mononuclear cells. Immunohistochemistry revealed prominent CD34+ dendritic cells in septal spaces, consistent with Nephrogenic Systemic Fibrosis (NSF). Seven years and two years prior she had received a gadolinium-based contrast agent (GBCA). She died due to NSF. Gross autopsy revealed a thickened and stenotic superior vena cava (SVC). Extensive fibrosis of the SVC, dermis, and subcutaneous tissue was noted, together with hyalinized collagen fibers within the muscular wall of the intestines and dura mater. These findings support the importance of skin changes in the recognition of life threatening extracutaneous tissue involvement in NSF.

Nephrogenic systemic fibrosis in a patient with renal failure demonstrating a "reverse superscan" on bone scintigraphy.

Nephrogenic systemic fibrosis (NSF) has been linked to utilization of gadolinium-based contrast agents in patients with renal impairment. We present a 19-year-old female patient with end-stage renal failure presenting with joint pains and subcutaneous nodules. She had a prior gadolinium-enhanced magnetic resonance angiography when she was 14 years old. Clinical findings revealed firm subcutaneous nodules in both thighs. Whole-body bone scan demonstrates tracer uptake predominantly in the soft tissues and muscles of the extremities with minimal bony uptake. Incisional biopsy of the left thigh nodule revealed features of NSF with a total pathological score of 4, highly consistent with NSF.

Nephrogenic systemic fibrosis: a systemic fibrosing disease resulting from gadolinium exposure.

Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs) during imaging procedures. NSF is characterised by skin thickening, tethering and hyperpigmentation; flexion contractures of joints; and extracutaneous fibrosis. This article reviews the history, clinical manifestations, epidemiology, histopathology and pathophysiology of this disabling disease.

Nephrogenic systemic fibrosis in the podiatric patient.

Nephrogenic systemic fibrosis (NSF) is a severely debilitating disease that was first described in the literature by Cowper and colleagues in 2000. It is pertinent to the field of podiatry because patients with NSF first manifest cutaneous symptoms in the lower extremity in the form of fibrosing lesions. To date, these lesions have been documented only in people with moderate to severe kidney failure. There is speculation that gadolinium, used as a contrast agent for imaging, might be the inciting factor that triggers a cascade of events that results in the inappropriate fibrosis both in the dermis and in deeper tissues. Nephrogenic systemic fibrosis has been shown to cause these lesions in the lungs, pleura, diaphragm, myocardium, pericardium, and dura mater, the presence of which are typically indicative of severe progression of NSF. In cases where the lesions are manifest in the periarticular tissue, joint contractures and restricted range of motion can often result. We provide a quick synopsis of NSF, and a short case study that describes the authors' experience with one of their patients who requested a surgical consult as a result of being wheelchair-bound due to NSF's sequelae.

Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a systemic disorder of patients with severe renal insufficiency who have received gadolinium (Gd)-based magnetic resonance contrast agents (GBCAs). The causative association with Gd exposure was strengthened by the demonstration of Gd in various tissues of NSF patients, predominantly at the bulk chemical level. The distribution of Gd at the histologic level of organs other than skin has not been reported previously. METHODS: We analysed tissues from an autopsy case with verified advanced NSF by light microscopy and scanning electron microscopy/energy-dispersive X-ray spectroscopy. Furthermore, we reviewed published literature to compare the histological and histochemical findings in NSF patients and chronic renal failure (CRF) patients without NSF. RESULTS: Insoluble Gd-phosphate deposits were detected in the skin, liver, lungs, intestinal wall (ileum), kidney, lymph node, skeletal muscle, dura mater and cerebellum of the NSF autopsy case, primarily in vascular walls. Some, but not all, Gd deposits were seen in fibrotic areas. Literature review highlighted that non-specific tissue fibrosis and calcification are frequent findings in tissues of patients with CRF with and without NSF. CONCLUSIONS: Vascular and extracellular Gd deposits are found in multiple organs of NSF patients, associated with calcification, and often in fibrotic areas. Gd deposits are not seen in patients with CRF unexposed to GBCAs but rarely may be seen in GBCA-exposed patients without clinical signs of NSF. Apart from diagnostic findings in skin, fibrosis of muscle and dura may be more prominent in NSF patients. Our findings should stimulate further investigation of mechanisms of fibrosis and pathologic calcification.

"Carcinoid-like" tricuspid valvulopathy associated with nephrogenic systemic fibrosis.

We present a case of a patient with end-stage renal disease and nephrogenic fibrosing dermopathy (NFD) whose echocardiogram demonstrated rare tricuspid valve abnormality with malcoaptation due to tethering and restricted motion of the leaflets causing severe tricuspid regurgitation. The cardiac abnormalities developed 3 years after her initial diagnosis of NFD was made by skin biopsy. The echocardiographic appearance of the tricuspid valve resembled that seen in patients with carcinoid heart disease; however, an evaluation for carcinoid tumor in our patient was negative. Myocardial biopsy performed at the time of right heart catheterization demonstrated trace gadolinium within the lysosomes of one cardiac fibroblast. This report is the first to describe the association between nephrogenic systemic fibrosis and severe valvular heart disease requiring valve replacement.

Proteome analysis of bronchoalveolar lavage fluid in lung fibrosis associated with systemic sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated. METHODS: To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). RESULTS: We analyzed spots over the range of 10.1kDa to 207.4kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including α2-macroglobulin, α1-antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including α2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients. CONCLUSIONS: In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc.

Nephrogenic systemic fibrosis: a review.

Nephrogenic systemic fibrosis (NSF) is a recently described, debilitating systemic disease most commonly seen in patients with renal insufficiency. Exposure to gadolinium-containing contrast agent has been associated with the onset of symptoms. The epidemiology, pathogenesis, clinical manifestation, diagnosis, histolopathology, differential diagnosis and treatment will be reviewed. Clinicians should have a high index of suspicion in susceptible individuals.

Cardiac autotransplantation for aortic and mitral valve replacement in a patient with nephrogenic systemic fibrosis.

Adequate exposure is a prerequisite for open valve surgery. The mitral valve can rarely be very challenging to expose. We describe a redo double valve replacement in a patient with nephrogenic systemic fibrosis in whom exposure of the mitral valve was achieved with cardiac autotransplantation.

Nephrogenic systemic fibrosis: an unusual scleroderma-like fibrosing disorder.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder, recently described in patients with advanced chronic kidney disease, usually after exposure to gadolinium (Gd)-based contrast agents, characterized by progressive fibrotic involvement mainly of the skin. At clinical examination, the cutaneous findings of NSF may partly resemble those of systemic sclerosis. However, the different topographic distribution of the skin thickening and hardening, usually involving the limbs and trunk, whilst sparing the face, the lack of serologic abnormalities and the distinctive histopathological findings allow this new disease entity to be distinguished from systemic sclerosis and other scleroderma-like fibrosing disorders (scleromyxedema, scleredema, eosinophilic fasciitis, etc.). Herein, we describe what, to best of our knowledge, is the first, biopsy proven, Italian case of NSF, which highlights the issue of the differential diagnosis between NSF and scleroderma-like fibrosing disorders.